Use of an alternative method to evaluate erythema severity in a clinical trial: difference in vehicle response with evaluation of baseline and postdose photographs for effect of oxymetazoline cream 1·0% for persistent erythema of rosacea in a phase IV study.

BackgroundOnce-daily topical oxymetazoline cream 1·0% significantly reduced persistent facial erythema of rosacea in trials requiring live, static patient assessments.ObjectivesTo evaluate critically the methodology of clinical trials that require live, static patient assessments by determining whether assessment of erythema is different when reference to the baseline photograph is allowed.MethodsIn two identically designed, randomized, phase III trials, adults with persistent facial erythema of rosacea applied oxymetazoline or vehicle once daily. This phase IV study evaluated standardized digital facial photographs from the phase III trials to record ≥ 1-grade Clinician Erythema Assessment (CEA) improvement at 1, 3, 6, 9 and 12 h postdose.ResultsAmong 835 patients (oxymetazoline n = 415, vehicle n = 420), significantly greater proportions of patients treated with oxymetazoline vs. vehicle achieved ≥ 1-grade CEA improvement. For the comparison between phase IV study results and the original phase III analysis, when reference to baseline photographs was allowed while evaluating post-treatment photographs, the results for oxymetazoline were similar to results of the phase III trials (up to 85.7%), but a significantly lower proportion of vehicle recipients achieved ≥ 1-grade CEA improvement (up to 29.7% [phase 4] vs. 52.3% [phase 3]; P<0.001). In the phase IV study, up to 80·2% of patients treated with oxymetazoline achieved at least moderate erythema improvement vs. up to 22·9% of patients treated with vehicle. The association between patients' satisfaction with facial skin redness and percentage of erythema improvement was statistically significant.ConclusionsAssessment of study photographs, with comparison to baseline, confirmed significant erythema reduction with oxymetazoline on the first day of application. Compared with the phase III trial results, significantly fewer vehicle recipients attained ≥ 1-grade CEA improvement, suggesting a mitigated vehicle effect. This methodology may improve the accuracy of clinical trials evaluating erythema severity

Analysis of drug resistance determinants in Klebsiella pneumoniae isolates from a tertiary-care hospital in Beijing, China.

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T helper cell subsets specific for pseudomonas aeruginosa in healthy individuals and patients with cystic fibrosis

Background: We set out to determine the magnitude of antigen-specific memory T helper cell responses to Pseudomonas aeruginosa in healthy humans and patients with cystic fibrosis. Methods: Peripheral blood human memory CD4+ T cells were co-cultured with dendritic cells that had been infected with different strains of Pseudomonas aeruginosa. The T helper response was determined by measuring proliferation, immunoassay of cytokine output, and immunostaining of intracellular cytokines. Results: Healthy individuals and patients with cystic fibrosis had robust antigen-specific memory CD4+ T cell responses to Pseudomonas aeruginosa that not only contained a Th1 and Th17 component but also Th22 cells. In contrast to previous descriptions of human Th22 cells, these Pseudomonal-specific Th22 cells lacked the skin homing markers CCR4 or CCR10, although were CCR6+. Healthy individuals and patients with cystic fibrosis had similar levels of Th22 cells, but the patient group had significantly fewer Th17 cells in peripheral blood. Conclusions: Th22 cells specific to Pseudomonas aeruginosa are induced in both healthy individuals and patients with cystic fibrosis. Along with Th17 cells, they may play an important role in the pulmonary response to this microbe in patients with cystic fibrosis and other conditions

A combinatorial TIR1/AFB–Aux/IAA co-receptor system for differential sensing of auxin

The plant hormone auxin regulates virtually every aspect of plant growth and development. Auxin acts by binding the F-box protein transport inhibitor response 1 (TIR1) and promotes the degradation of the AUXIN/INDOLE-3-ACETIC ACID (Aux/IAA) transcriptional repressors. Here we show that efficient auxin binding requires assembly of an auxin co-receptor complex consisting of TIR1 and an Aux/IAA protein. Heterologous experiments in yeast and quantitative IAA binding assays using purified proteins showed that different combinations of TIR1 and Aux/IAA proteins form co-receptor complexes with a wide range of auxin-binding affinities. Auxin affinity seems to be largely determined by the Aux/IAA. As there are 6 TIR1/AUXIN SIGNALING F-BOX proteins (AFBs) and 29 Aux/IAA proteins in Arabidopsis thaliana, combinatorial interactions may result in many co-receptors with distinct auxin-sensing properties. We also demonstrate that the AFB5–Aux/IAA co-receptor selectively binds the auxinic herbicide picloram. This co-receptor system broadens the effective concentration range of the hormone and may contribute to the complexity of auxin response

Turnip mosaic potyvirus probably first spread to Eurasian brassica crops from wild orchids about 1000 years ago

Turnip mosaic potyvirus (TuMV) is probably the most widespread and damaging virus that infects cultivated brassicas worldwide. Previous work has indicated that the virus originated in western Eurasia, with all of its closest relatives being viruses of monocotyledonous plants. Here we report that we have identified a sister lineage of TuMV-like potyviruses (TuMV-OM) from European orchids. The isolates of TuMV-OM form a monophyletic sister lineage to the brassica-infecting TuMVs (TuMV-BIs), and are nested within a clade of monocotyledon-infecting viruses. Extensive host-range tests showed that all of the TuMV-OMs are biologically similar to, but distinct from, TuMV-BIs and do not readily infect brassicas. We conclude that it is more likely that TuMV evolved from a TuMV-OM-like ancestor than the reverse. We did Bayesian coalescent analyses using a combination of novel and published sequence data from four TuMV genes [helper component-proteinase protein (HC-Pro), protein 3(P3), nuclear inclusion b protein (NIb), and coat protein (CP)]. Three genes (HC-Pro, P3, and NIb), but not the CP gene, gave results indicating that the TuMV-BI viruses diverged from TuMV-OMs around 1000 years ago. Only 150 years later, the four lineages of the present global population of TuMV-BIs diverged from one another. These dates are congruent with historical records of the spread of agriculture in Western Europe. From about 1200 years ago, there was a warming of the climate, and agriculture and the human population of the region greatly increased. Farming replaced woodlands, fostering viruses and aphid vectors that could invade the crops, which included several brassica cultivars and weeds. Later, starting 500 years ago, inter-continental maritime trade probably spread the TuMV-BIs to the remainder of the world

Nosocomial Co-Transmission of Avian Influenza A(H7N9) and A(H1N1)pdm09 Viruses between 2 Patients with Hematologic Disorders

A nosocomial cluster induced by co-infections with avian influenza A(H7N9) and A(H1N1)pdm09 (pH1N1) viruses occurred in 2 patients at a hospital in Zhejiang Province, China, in January 2014. The index case-patient was a 57-year-old man with chronic lymphocytic leukemia who had been occupationally exposed to poultry. He had co-infection with H7N9 and pH1N1 viruses. A 71-year-old man with polycythemia vera who was in the same ward as the index case-patient for 6 days acquired infection with H7N9 and pH1N1 viruses. The incubation period for the second case-patient was estimated to be <4 days. Both case-patients died of multiple organ failure. Virus genetic sequences from the 2 case-patients were identical. Of 103 close contacts, none had acute respiratory symptoms; all were negative for H7N9 virus. Serum samples from both case-patients demonstrated strong proinflammatory cytokine secretion but incompetent protective immune responses. These findings strongly suggest limited nosocomial co-transmission of H7N9 and pH1N1 viruses from 1 immunocompromised patient to another.published_or_final_versio

Diffractive Higgs Production by AdS Pomeron Fusion

The double diffractive Higgs production at central rapidity is formulated in terms of the fusion of two AdS gravitons/Pomerons first introduced by Brower, Polchinski, Strassler and Tan in elastic scattering. Here we propose a simple self-consistent holographic framework capable of providing phenomenologically compelling estimates of diffractive cross sections at the LHC. As in the traditional weak coupling approach, we anticipate that several phenomenological parameters must be tested and calibrated through factorization for a self-consistent description of other diffractive process such as total cross sections, deep inelastic scattering and heavy quark production in the central region.Comment: 53 pages, 8 figure

Morbidity related to defunctioning ileostomy closure after ileal pouch-anal anastomosis and low colonic anastomosis

Purpose Defunctioning ileostomies are widely performed in order to prevent or treat anastomotic leakage after colorectal surgery. The aim of the present study was to determine morbidity related to stoma closure and to identify predictive factors of a complicated postoperative course. Methods A consecutive series of 138 patients were retrospectively analyzed after stoma reversal. Data collection included general demographics and surgery-related aspects. Morbidity related to stoma closure was retrieved from our prospectively collected registry of complications. Results In 74 of 138 patients, defunctioning ileostomy was performed after restorative proctocolectomy and ileal pouchanal anastomosis (IPAA). The remaining ileostomies (n=64) were constructed after a low colorectal or coloanal anastomosis. A total of 46 complications were recorded in 28 patients resulting in an overall complication rate of 20.3%. Anastomotic leakage rate was 4.3%, and reoperation rate was 8.0%. The number of complications according to the Clavien-Dindo classification was 5 for grade I (10.9%), 26 for grade II (56.5%), 13 for grade III (28.3%), 1 for grade IV (2.2%), and 1 for grade V (2.2%). Multivariate analysis revealed a significantly higher ASA score in the complicated group (P=0.015, odds ratio 2.6, 95% confidence interval 1.2-5.6). Conclusions Closure of a defunctioning ileostomy is associated with 20% morbidity and a reoperation rate of 8%. There is an urgent need for criteria on which a more selective use of a defunctioning ileostomy after low colonic anastomosis or IPAA can be based given its associated morbidit

Feasibility, reliability and validity of a questionnaire on healthcare consumption and productivity loss in patients with a psychiatric disorder (TiC-P)

Background: Patient self-report allows collecting comprehensive data for the purpose of performing economic evaluations. The aim of the current study was to assess the feasibility, reliability and a part of the construct validity of a commonly applied questionnaire on healthcare utilization and productivity losses in patients with a psychiatric disorder (TiC-P). Methods. Data were derived alongside two clinical trials performed in the Netherlands in patients with mental health problems. The response rate, average time of filling out the questionnaire and proportions of missing values were used as indicators of feasibility of the questionnaire. Test-retest analyses were performed including Cohen's kappa and intra class correlation coefficients to assess reliability of the data. The construct validity was assessed by comparing patient reported data on contacts with psychotherapists and reported data on long-term absence from work with data derived from registries. Results: The response rate was 72%. The mean time needed for filling out the first TiC-P was 9.4 minutes. The time needed for filling out the questionnaire was 2.3 minutes less for follow up measurements. Proportions of missing values were limited (< 2.4%) except for medication for which in 10% of the cases costs could not be calculated. Cohen's kappa was satisfactory to almost perfect for most items related to healthcare consumption and satisfactory for items on absence from work and presenteeism. Comparable results were shown by the ICCs on variables measuring volumes of medical consumption and productivity losses indicating good reliability of the questionnaire. Absolute agreement between patient-reported data and data derived from medical registrations of the psychotherapists was satisfactory. Accepting a margin o